NM_024675.4(PALB2):c.212-2A>G AND Familial cancer of breast

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 22, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000206312.21

Allele description [Variation Report for NM_024675.4(PALB2):c.212-2A>G]

NM_024675.4(PALB2):c.212-2A>G

Gene:

PALB2:partner and localizer of BRCA2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p12.2

Genomic location:

Preferred name:

NM_024675.4(PALB2):c.212-2A>G

HGVS:

NC_000016.10:g.23636336T>C
NG_007406.1:g.10022A>G
NM_001407296.1:c.152-2A>G
NM_001407297.1:c.212-2A>G
NM_001407298.1:c.212-2A>G
NM_001407299.1:c.212-2A>G
NM_001407300.1:c.212-2A>G
NM_001407301.1:c.212-2A>G
NM_001407302.1:c.212-2A>G
NM_001407304.1:c.-674-2A>G
NM_001407305.1:c.-674-2A>G
NM_001407306.1:c.-674-2A>G
NM_001407307.1:c.-674-2A>G
NM_001407308.1:c.-674-2A>G
NM_001407309.1:c.-674-2A>G
NM_001407310.1:c.-674-2A>G
NM_001407311.1:c.-674-2A>G
NM_001407312.1:c.-105+4774A>G
NM_001407313.1:c.-105+4774A>G
NM_001407314.1:c.48+4774A>G
NM_024675.4:c.212-2A>GMANE SELECT
LRG_308t1:c.212-2A>G
LRG_308:g.10022A>G
NC_000016.9:g.23647657T>C
NM_024675.3:c.212-2A>G

Links:

dbSNP: rs730881879

NCBI 1000 Genomes Browser:

rs730881879

Molecular consequence:

NM_001407312.1:c.-105+4774A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001407313.1:c.-105+4774A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001407314.1:c.48+4774A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001407296.1:c.152-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407297.1:c.212-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407298.1:c.212-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407299.1:c.212-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407300.1:c.212-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407301.1:c.212-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407302.1:c.212-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407304.1:c.-674-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407305.1:c.-674-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407306.1:c.-674-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407307.1:c.-674-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407308.1:c.-674-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407309.1:c.-674-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407310.1:c.-674-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407311.1:c.-674-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_024675.4:c.212-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:: Familial cancer of breast
Synonyms:: Breast cancer, familial; Hereditary breast cancer
Identifiers:: MONDO: MONDO:0016419; MedGen: C0346153; OMIM: 114480

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000261091	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 22, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26681312, 30890586, 28492532
SCV000677809	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Likely pathogenic (Aug 17, 2015)	unknown	clinical testing	Citation Link,
SCV000919928	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Dec 14, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001481177	Baylor Genetics - CSER-TexasKidsCanSeq	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 1, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Alternative splicing and ACMG-AMP-2015-based classification of PALB2 genetic variants: an ENIGMA report.

Lopez-Perolio I, Leman R, Behar R, Lattimore V, Pearson JF, Castéra L, Martins A, Vaur D, Goardon N, Davy G, Garre P, García-Barberán V, Llovet P, Pérez-Segura P, Díaz-Rubio E, Caldés T, Hruska KS, Hsuan V, Wu S, Pesaran T, Karam R, Vallon-Christersson J, et al.

J Med Genet. 2019 Jul;56(7):453-460. doi: 10.1136/jmedgenet-2018-105834. Epub 2019 Mar 19.

PubMed [citation]

PMID:: 30890586
PMCID:: PMC6591742

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000261091.12

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change affects an acceptor splice site in intron 3 of the PALB2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs730881879, gnomAD 0.001%). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 182757). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 30890586; Invitae). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000677809.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919928.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Variant summary: PALB2 c.212-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.6e-06 in 217494 control chromosomes. c.212-2A>G has been reported in the literature in one individual affected with Breast Cancer (Susswein_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics - CSER-TexasKidsCanSeq, SCV001481177.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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